Vitamin D is a fat-soluble nutrient that behaves more like a prohormone, a substance the body converts into a hormone. Unlike other vitamins that must be obtained solely from diet, the body can synthesize it. This characteristic places it at the start of a metabolic journey that transforms it into a signaling molecule influencing many physiological processes.
Sources and Initial Synthesis of Vitamin D
The body acquires vitamin D through two primary routes: skin production and intake from diet or supplements. The most significant source is synthesis via sunlight. When ultraviolet B (UVB) radiation from the sun strikes the skin, it converts a cholesterol precursor into vitamin D3. This process depends on factors like season, time of day, skin pigmentation, and geographic latitude.
Dietary sources provide two main forms. Vitamin D3, or cholecalciferol, is in animal-based foods like fatty fish, fish liver oils, and egg yolks. Vitamin D2, or ergocalciferol, comes from plant-based sources like mushrooms exposed to UV light. Both forms are also available as supplements and used to fortify foods.
Both D2 and D3 are transported to the liver to begin activation. However, research indicates that vitamin D3 is more potent and stable than an equivalent amount of vitamin D2. This makes D3 the more efficient form for correcting a deficiency and maintaining adequate status.
The Activation Process in the Liver and Kidneys
Vitamin D from sun or diet is biologically inert and must undergo a two-step activation process. This transformation begins in the liver. After entering the bloodstream, both vitamin D2 and D3 are transported to the liver for their first chemical modification, a process called hydroxylation, where a hydroxyl group (one oxygen and one hydrogen atom) is added to the molecule.
In the liver, the enzyme 25-hydroxylase (CYP2R1) converts the initial vitamin D into 25-hydroxyvitamin D, also called calcidiol. Calcidiol is the major circulating form of vitamin D and is what doctors measure in blood tests to assess a person’s status. While it is the primary storage form, calcidiol has limited biological activity on its own.
The final activation step occurs mainly in the kidneys. Calcidiol travels from the liver through the bloodstream to the kidneys for a second hydroxylation. Here, the enzyme 1-alpha-hydroxylase (CYP27B1) adds another hydroxyl group, converting calcidiol into 1,25-dihydroxyvitamin D, known as calcitriol.
Calcitriol is the fully active, hormonal form of vitamin D. It is responsible for carrying out the majority of vitamin D’s functions throughout the body. This two-step conversion ensures the production of the hormone is tightly controlled.
How Vitamin D Metabolism is Regulated
The body has a control system to manage the final activation of vitamin D, ensuring calcitriol levels are precisely managed. This regulation primarily revolves around maintaining calcium balance in the blood. The main controller is parathyroid hormone (PTH), secreted by the parathyroid glands.
This process operates as a feedback loop. When blood calcium levels drop, the parathyroid glands increase their secretion of PTH. PTH then travels to the kidneys and stimulates the 1-alpha-hydroxylase enzyme, accelerating the conversion of stored calcidiol into active calcitriol.
The newly produced calcitriol works to raise blood calcium levels. Once concentrations return to normal, the parathyroid glands reduce PTH secretion. This drop in PTH slows the production of calcitriol, and calcitriol itself also signals the glands to suppress PTH synthesis. This tightly regulated mechanism ensures that calcium levels remain stable.
The Bodily Functions of Active Vitamin D
Once activated to calcitriol, vitamin D regulates calcium and phosphorus, which are needed for building and maintaining the skeleton. Calcitriol’s primary site of action is the small intestine. It binds to the vitamin D receptor (VDR), triggering gene expression that produces calcium-transporting proteins and increases mineral absorption from diet.
By ensuring a sufficient supply of these minerals, calcitriol facilitates bone mineralization. Without adequate calcitriol, the body cannot absorb enough calcium, leading to rickets in children and osteomalacia in adults. The hormone also works with PTH to mobilize calcium from bone and reduce its loss through the kidneys.
Beyond bone health, calcitriol influences other bodily systems, as the vitamin D receptor is found in nearly every cell type. Calcitriol helps modulate the immune system by regulating cells like T-cells and macrophages. It also plays a part in controlling cell growth and differentiation.
Factors That Impair Vitamin D Metabolism
While poor intake can cause deficiency, certain health conditions can impair the body’s ability to metabolize vitamin D. These issues disrupt the conversion pathway, meaning the body cannot produce enough calcitriol even with adequate initial supply. The liver and kidneys are central to this process.
Severe liver disease, such as cirrhosis, can compromise the first activation step. A damaged liver may have a reduced capacity to perform 25-hydroxylation. This limits the amount of calcidiol available for the final activation step in the kidneys.
Chronic kidney disease (CKD) is a more common cause of impaired metabolism. As kidney function declines, the activity of the 1-alpha-hydroxylase enzyme is reduced, hindering the conversion of calcidiol to active calcitriol. This impairment is worsened by other hormonal changes that occur in CKD, which directly suppress the activating enzyme. Consequently, patients with CKD often have low levels of active vitamin D despite normal levels of the storage form.
In rarer cases, genetic disorders can affect the activating enzymes. Mutations in the gene for the 1-alpha-hydroxylase enzyme can cause vitamin D-dependent rickets type 1. Individuals with this disorder cannot produce calcitriol and require treatment with the active hormone to prevent bone disease.